Physicochemical evaluation and in vitro release studies on itraconazolium sulfate salt (original) (raw)
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Ditosylate Salt of Itraconazole and Dissolution Enhancement Using Cyclodextrins
AAPS PharmSciTech, 2012
Salt formation has been a promising approach for improving the solubility of poorly soluble acidic and basic drugs. The aim of the present study was to prepare the salt form of itraconazole (ITZ), a hydrophobic drug to improve the solubility and hence dissolution performance. Itraconazolium ditolenesulfonate salt (ITZDITOS) was synthesized from ITZ using acid addition reaction with p-toluenesulfonic acid. Salt characterization was performed using 1 H NMR, mass spectrometry, Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. The particle size and morphology was studied using dynamic light scattering technique and scanning electron microscopy, respectively. The solubility of the salt in water and various pharmaceutical solvents was found multifold than ITZ. The dissolution study exhibited 5.5-fold greater percentage release value in 3 h of ITZDITOS (44.53%) as compared with ITZ (8.54%). Results of in vitro antifungal studies using broth microdilution technique indicate that ITZDITOS possessed similar antifungal profile as that of ITZ when tested against four fungal pathogens. Furthermore, the physical mixtures of ITZDITOS with two cyclodextrins, βcyclodextrin (β-CD), and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) were prepared in different molar ratios and were evaluated for in vitro release. It was observed that in only 30 min of dissolution study, about 74 and 81% of drug was released from 1:3 molar ratios of ITZDITOS with β-CD and ITZDITOS with HP-β-CD, respectively, which was distinctly higher than the drug released from ITZ commercial capsules (70%). The findings warrant further preclinical and clinical studies on ITZDITOS so that it can be established as an alternative to ITZ for developing oral formulations.
Comparative study of itraconazole-cyclodextrin inclusion complex and its commercial product
Archives of Pharmacal Research, 2010
Itraconazole (ITZ) solid complex using hydroxypropyl-β-cyclodextrin (ITZ-HP-β-CD) with 20% polyvinylpyrrolidone was prepared by a co-evaporation method. The complex improved antifungal activity against C. parapasilosis and C. albicans. The complex demonstrated good flow and compressibility characteristics. The complex was formulated as a capsule dosage form and drug release was evaluated. Capsules containing ITZ-HP-β-CD at a molar ratio of 1:3 with 20% polyvinylpyrrolidone have a faster dissolution rate than commercial capsules (Sporanox ® ). About 88% of ITZ was released in less than 30 min and the initial dissolution rate exhibited a 3.5-fold increase compared to the commercial product. UV spectrophotometeric, HPLC, and antimicrobial methods were used to determine ITZ concentration in the release medium and the results obtained by these methods are reported. It was found that HPLC analysis is a suitable and reliable method for determination of the drug concentration with a coefficient of variation less than 10%. The intraday precision showed a coefficient of variation less than 3.96%, and that for interday was less than 4.99%. The HPLC method was more accurate and precise than the antimicrobial and UV-spectrophotometric methods for determination of ITZ concentration present in the release medium.
Iraqi Journal of Pharmaceutical Sciences ( P-ISSN: 1683 - 3597 , E-ISSN : 2521 - 3512), 2019
Itraconazole is a triazole antifungal given orally for the treatment of oropharyngeal and vulvovaginal candidiasis, for systemic infections including aspergillosis, candidiasis, and for the prophylaxis of fungal infections in immunocompromised patients. The study aimed to formulate a practical water-insoluble Itraconazole, with insufficient bioavailability as nanosuspension to increase aqueous solubility and improve its dissolution and oral bioavailability. Itraconazole nanosuspension was produced by a solvent-antisolvent nanoprecipitation method in the presence of different stabilisers (Poloxamer-188, HPMCE5) at different ratios with the drug alone or combination with surfactant(tween 80, SLS). The results exhibit that the particle sizes of all prepared itraconazole formulations were in the nano size. The best formula (F6) has a particle size. ( 42 ) nm and Zeta potential of (- 21.86 ) mV. In vitro cumulative release from the nanosuspe...
Formulation of betacyclodextrin based nanosponges of itraconazole
Journal of Inclusion Phenomena and Macrocyclic Chemistry, 2007
Nanosponges are betacyclodextrins crosslinked with carbonate bonds. The polymer formed is nanoparticulate in nature. Itraconazole is a BCS Class II drug that has a dissolution rate limited poor bioavailability. Rationale of the work was to enhance the solubility of Itraconazole so that the bioavailability problems are solved. Solid dispersion technique has been used for drug incorporation. The effect of a ternary component copolyvidonum on solubility of itraconazole has been studied. Phase solubility studies has been carried out with a rationale of comparing the solubilization efficiency of nanosponges, copolyvidonum and combination. The dispersions were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and photon correlation spectroscopy (PCS). It was found that the solubility of itraconazole was enhanced more than 50-folds with a ternary solid dispersion system. Using copolyvidonum in conjunction with nanosponges helps to increase the solubilization efficiency of nanosponges as evident from the phase solubility studies.
The aim of the present work is to utilize the nanotechnology for preparing stable nanoparticles that enhance the dissolution and hence the bioavailability of poorly water-soluble Itraconazole (ITZ). ITZ nanosuspensions were produced by nanoprecipitation method in the presence of surfactant (tween 80) and selected stabilizers (HPMC, PVP K 17 and Pluronic F 68) at different ratios with the drug. The nanosuspensions were evaluated for their physicochemical properties and drug content. The nanoparticles were prepared by lyophilization technique and characterized by morphology evaluation, Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The optimized formulation showed an average particles size of 213.56 ± 19.58 nm and Zeta potential of-18.35 ± 2.55 mV. In vitro cumulative release from the nanosuspension was 85.64% at 60 min when compared to pure drug 35.52% and freeze dried nanoparticles 93.81%. Pharmacokinetic studies revealed that AUC(0–36) was increased by two folds when ITZ nanoparticles were administered orally compared with the market formulation (Sporanox ®), which in turn increased the bioavailability. Thus, Nanoparticles seems to be a promising approach for increasing the dissolution and enhancement the bioavailability of ITZ.
Asian Journal of Pharmaceutical and Clinical Research, 2018
Objective: The objective of this study was to prepare and evaluate itraconazole (ITZ) nanosuspensionsusing polymer Eudragit RL-100 and stabilizer Tween-80 by nanoprecipitation method. Materials and Methods: Itraconazole is a potent broad-spectrum Biopharmaceutical Classification System Class II triazole antifungal drug. Nanosuspensions were prepared using solvent displacement/nanoprecipitation method with the help of Eudragit RL-100 as rate-controlled polymer in different ratios and using Tween-80 as stabilizer. The nanosuspension preparation was optimized for particle size by investigating two factors that are solvent:anti-solvent ratio and surfactant concentration, at three levels. The prepared nanosuspensions were evaluated and characterized for particle size, drug excipient compatibility, percentage yield, drug entrapment efficiency, surface morphology, zeta potential, saturation solubility, solid state, and in vitro drug release studies. Results: The nanosuspensions of itraconazole were successfully prepared using solvent displacement/nanoprecipitation method. The two factors solvent: anti-solvent ratio and surfactant concentration influenced the particle size of the nanosuspensions prepared. The Fourier-transform infrared spectroscopy studies confirmed that drug and excipients are compatible, and the X-ray powdered diffraction and differential scanning calorimetry results indicated that the nanoprecipitation method led to the amorphization of itraconazole. Itraconazolenanosuspensions increased the saturation solubility to an extent of 4 times. Itraconazole nanosuspensions completely dissolved in the dissolution medium within 10 s and 72% drug release within 5 min, while the pure drug was dissolved only up to 20% in 15 min and nanosuspensions showed increased dissolution rate of 3 folds, the active drug. Conclusions: Stable itraconazole nanosuspensions were successfully prepared and these nanosuspensions demonstrated dramatic improvement in dissolution rate of the active drug.
European Journal of Pharmaceutical Sciences, 2008
Solubility Itraconazole Supersaturation Co-solvent/solvent quench approach a b s t r a c t Cyclodextrins can increase the apparent solubility and dissolution rate of poorly watersoluble drug candidates improving their biopharmaceutical performance. The current data assess the ability of hydrophilic cyclodextrins to solubilize compounds via stabilization of supersaturated drug solutions presumably by inhibition of nucleation and arresting crystal growth. To these points, the effects of 2-hydroxypropyl--cyclodextrin (HPCD) and sulfobutylether--cyclodextrin (SBECD) on equilibrium solubility was assessed via phasesolubility analysis as were the interactions of these excipients on drug solubility under conditions favoring supersaturation. Phase-solubility analysis indicated that different profiles were generated as a function of the cyclodextrin examined and the pH of the complexing medium. When kinetic solubility measurements were completed, the cyclodextrins were found to stabilize concentrations of itraconazole significantly in excess of their equilibrium solubility when supersaturated solutions were formed using the co-solvent/solvent quench approach. These solutions were stable over 240 min falling in concentration at the 24 h time point of the experiment unlike those formed using surfactants and other polymers which demonstrated a rapid decrease in concentration over time. These data suggest that hydrophilic cyclodextrins might be useful formulation adjuncts in supersaturating drug delivery systems. (M.E. Brewster).
Journal of Drug Delivery and Therapeutics, 2020
The aim of this work is the enhancement of the hydrosolubility behaviour of a poorly soluble, weakly basic drug, using itraconazole (ITZ) as a case example. Binary inclusion complexes of ITZ with β-cyclodextrin (β-CD) are prepared in 1:2 molar ratios of ITZ to β-CD by co-evaporation method. Both solubility and dissolution behaviour are compared with that of the pure drug. Ternary complexes can be obtained by adding the polyvinylpirrolidone (PVP) which is a highly water soluble polymer, in the ITZ/ β-CD complex formation. Actually, Solid state analysis is performed for all formulations and for pure ITZ applying the Fourier transforms infrared (FT-IR) spectroscopy, powder X-ray diffraction (pX-RD) and differential scanning calorimetry (DSC). Solubility tests indicate that with all formulation, the solubility of ITZ formed with β-CD or β-CD and PVP proved to be increased. The obtained results show that the pure drug has a poor dissolution property, and the ternary inclusion complexes r...
Itraconazole (ITZ), a broad spectrum antifungal, is used orally for the treatment of wide range of systemic fungal diseases; it's extremely poor water solubility mainly causes erratic absorption and low bioavailability. This study aimed to prepare ITZ oral nanosuspensions with enhanced stability and dissolution rate for paediatrics and geriatrics who finds difficulty in swallowing. A simple and scalable, acid-base precipitation method was adopted. Methylcellulose (MC) was investigated as a new stabilizer among other polymeric and surfactant stabilizers including poloxamer 188 (P188), poloxamer 407 (p407), sodium lauryl sulphate (SLS), polyvinyl pyrrolidone K25 (PVP) and hydroxypropylmethylcellulose E15 (HPMC) at different concentrations. The results revealed that all formulations, except for those stabilized with PVP, were in sub-micron ranges of 314-968 nm and polydispersity index of less than 0.4. Thermal analysis, X-ray diffraction studies and scanning electron microscope imaging showed reduced crystallinity of ITZ, which resulted in enhanced dissolution rate of 10-110 fold increases in the dissolution efficiency (DE) for the prepared nanosuspension compared to untreated ITZ and comparable to the commercially available product. MC proved to be successful in achieving a stable nanosuspension.
Journal of Pharmaceutical and Biomedical Analysis, 2007
The main objective of this study was to improve the inclusion formation between itraconazole and -cyclodextrin and thus enhance dissolution amount and bioavailability characteristics of itraconazole. Inclusion complexes between itraconazole and -cyclodextrin were prepared using simple physical mixing, conventional coprecipitation method, and supercritical carbon dioxide (SC CO 2 ). Effects of process variables (temperature, pressure) and drug:cyclodextrin ratio on inclusion yield and thermal behavior of the solid complexes prepared by SC CO 2 were studied and compared to those obtained by physical mixing and coprecipitation methods. In addition, dissolution amounts of the products obtained by different methods were measured in gastric fluid. Finally, pharmacokinetic studies of the inclusion complexes were conducted in male Wistar rats to assess the bioavailability of the prepared complexes.